Defective factor XII causes hereditary angioedema

Defective factor XII causes hereditary angioedema Hereditary angioedema (HAE) is a rare life-threatening inherited edema disorder that is characterized by recurrent episodes of localized edema of the skin or of the mucosa of the gastrointestinal tract or upper airway. The edema formation in patients with HAE is primarily caused by a transient increased bradykinin release from high molecular weight kininogen (HK) due to uncontrolled activation of the coagulation factor XII (FXII)-dependent kallikrein kinin system (KKS) (Bossi F et al. 2009; Kaplan AP 2010; Suffritti C et al. 2014: Zuraw BL & Christiansen SC 2016). Angioedema initiated by bradykinin is usually associated with SERPING1 (C1-INH) deficiency. SERPING1 is the major regulator of the contact system. More rarely, HAE occurs in individuals with normal SERPING1 activity, and has been linked to mutations in other proteins, including FXII, plasminogen, and angiopoietin (Magerl M et al. 2017; Zuraw BL 2018; Ivanov I et al. 2019). Substitution of threonine 328 by either a lysine or an arginine residue (T328K or T328R) in the FXII proline-rich region has been identified in several families with HAE and normal SERPING1. FXII T328K or T328R variants change protein glycosylation and introduce a new site that is sensitive to enzymatic cleavage by fibrinolytic and coagulation proteases such as plasmin, thrombin, or FXIa (de Maat S et al. 2016; Ivanov I et al. 2019). The intrinsic capacity of the truncated form of FXII (329-615) (also known as δFXII) to convert prekallikrein to kallikrein is greater than that of FXII leading to more kallikrein generated early during reciprocal activation (Ivanov I et al. 2019). Second, FXII (329-615) is a better kallikrein substrate than is FXII. The accelerated kallikrein/FXII activation with truncated FXII (329-615) appears to overwhelm the regulatory function of SERPING1 at normal plasma levels leading to uncontrolled bradykinin formation (de Maat S et al. 2016; Ivanov I et al. 2019). Binding of the proinflammatory peptide hormone bradykinin to the bradykinin B2 receptor (B2R) activates various proinflammatory signaling pathways that increase vascular permeability and fluid efflux. An excessive formation of bradykinin due to uncontrolled activation of FXII-dependent KKS causes increased vascular permeability at the level of the postcapillary venule and results in HAE (Zuraw BL & Christiansen SC 2016; de Maat S et al. 2016; Ivanov I et al. 2019).